DESCRIPTION:(PROVIDED BY APPLICANT) The long-term goal of this proposal is to identify molecular events involved in breast cancer progression. Breast cancer is both a genetic and an endocrine disease. Genetic analysis of breast tumors and cell lines has revealed several commonly mutated genes; in particular, mutations in the p53 tumor suppressor gene occur in over half of the breast tumors studied. On the endocrine side, the roles of the steroid hormones 17B-estradiol (E2) and progesterone in proliferation, differentiation, and pathogenesis of mammary epithelial cells have been demonstrated by hormone ablation and by genetic manipulation of the mouse genome. In humans, estrogens appear to be important for early stage breast cancer. Paradoxically, as tumors progress, about one-third become ERa- and PR-negative. This is associated with poor response to anti-hormone therapy, a common form of treatment for breast cancer. However, the mechanisms of loss of ER expression and evolution of E2-independent tumor growth are not completely understood. We have developed a new mouse mammary tumor model using the Cre/lox system for tissue-specific inactivation of p53 mice carrying MMTV-Cre and floxed p53 alleles develop mammary tumors with nearly complete penetrance. Lung and/or liver metastases are found in 35 percent of these mice. Amplification of the cmyc proto-oncogene, a gene known to cooperate with the p.53 mutation in carcinogenesis, is frequently observed. Importantly, tumor progression is associated with the loss of ERa expression and Estrogen-independent growth. We hypothesize that activated proto-oncogenes promote E2-independent breast tumor growth. We propose to study the cellular and molecular events during breast cancer progression and ER loss in this new model. There are three aims: 1) To determine the onset of transition from ERa-positive to ERa-negative tumor and assess the role of ovarian hormones in tumor progression. We will study mechanisms involved in the loss of ERa expression and the effects of ERa re-expression have on the growth of p53(delta 5&6) mammary epithelial cells and p53(delta 5&6) ERa-negative tumor cells in vitro and in vivo. 2) To determine the mechanisms of c-myc overexpression and its impact on tumor progression. 3) To analyze the contribution of c-myc and deregulated Rb activities to loss of ERa expression and emergence of E2-independent growth. These proposed studies should provide significant insights into molecular events involved in breast cancer progression and critical information for anti-estrogen based breast cancer prevention and intervention.